College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China; National Engineering Research Center for Manufacturing Technology of TCM Solid Preparation, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.
National Engineering Research Center for Manufacturing Technology of TCM Solid Preparation, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.
Bioorg Chem. 2020 Jan;94:103390. doi: 10.1016/j.bioorg.2019.103390. Epub 2019 Oct 22.
Based on the approach of merged pharmacophores of GPR119 agonists and DPP-4 inhibitors, a series of tetrahydropyridopyrimidine compounds were designed as dual GPR119 and DPP-4 modulators with hypoglycemic activity. Seven fragments extracted from DPP-4 inhibitors were hybridized with the scaffold of tetrahydropyridopyrimidine. Among them, compound 51 displayed most potent GPR119 agonistic activity (EC = 8.7 nM) and good inhibition rate of 74.5% against DPP-4 at 10 μM. Furthermore, the blood glucose AUC of 51 was reduced to 19.5% in the oral glucose tolerance test (oGTT) at the dose of 30 mg/kg in C57BL/6N mice, which was more potent than that of vildagliptin (16.4%) at the same dose. The docking study of compound 51 with DPP-4 indicated GPR119 agonists could inhibit DPP-4 to serve as dual GPR119 and DPP-4 modulators.
基于 GPR119 激动剂和 DPP-4 抑制剂融合药效团的方法，设计了一系列具有降血糖活性的四氢吡啶嘧啶类化合物作为双重 GPR119 和 DPP-4 调节剂。从 DPP-4 抑制剂中提取的 7 个片段与四氢吡啶嘧啶骨架杂交。其中，化合物 51 表现出最强的 GPR119 激动活性（EC=8.7 nM），在 10 μM 时对 DPP-4 的抑制率为 74.5%。此外，在 C57BL/6N 小鼠中，化合物 51 在 30mg/kg 剂量下的口服葡萄糖耐量试验（oGTT）中的血糖 AUC 降低到 19.5%，其效力强于相同剂量下的维格列汀（16.4%）。化合物 51 与 DPP-4 的对接研究表明，GPR119 激动剂可以抑制 DPP-4，从而作为双重 GPR119 和 DPP-4 调节剂。
